Kumazawa Teruaki, Tsuchiya Norihiko, Wang Lizhong, Sato Kazunari, Kamoto Toshiyuki, Ogawa Osamu, Nakamura Akira, Kato Tetsuro, Habuchi Tomonori
Department of Urology, Akita University School of Medicine, Akita 010-8543, Japan.
Int J Cancer. 2004 May 20;110(1):140-4. doi: 10.1002/ijc.20070.
It is widely recognized that androgen biosynthesis and metabolism are associated with the development and progression of prostate cancer. The human CYP11A1 gene (CYP11A1) encodes the P450scc enzyme, which mediates the first step in sex steroid hormone synthesis. The gene contains a (tttta)n-5 bp tandem repeat microsatellite polymorphism located at 528 bp upstream of the translation initiation site and the CYP11A1 mRNA level may be modulated by the polymorphism. Recent studies suggested that the absence of the shortest (tttta)4 allele of the CYP11A1 polymorphism was associated with a risk of polycystic ovary syndrome and with a hyperandrogenic state in polycystic ovary syndrome patients. In our study which included 278 prostate cancer patients, 213 benign prostatic hyperplasia (BPH) patients and 299 male controls, we explored the association between the CYP11A1 polymorphism and prostate cancer on the hypothesis that the presence of the (tttta)4 allele may increase the risk of the development or progression of prostate cancer. In addition, we measured the serum levels of 6 steroid hormones or their metabolite (i.e., testosterone, free-testosterone, estrone, estradiol, dehydroepiandrosterone and androstendione) in 156 control males subjects and compared those with and without the (tttta)4 allele. The polymorphism was evaluated by PCR amplification of a 145-170 bp fragment followed by polyacrylamid gel electrophoresis. The CYP11A1 allele consisted of 4, 6, 7, 8 and 9 (tttta)-5 bp repeats. There was no significant difference in the genotype frequency as for the presence of the (tttta)4 allele between prostate cancer patients and male controls, and between prostate cancer patients and BPH patients. However, there was a significant difference in the genotype frequency in relation to the disease status. Prostate cancer patients without the (tttta)4 allele had an increased risk of metastatic disease (stage D) compared to those with the (tttta)4 allele [adjusted odds ratio (aOR)=1.76, 95% confidence interval (Cl)=1.07-2.90 and p =0.026]. Patients without the (tttta)4 allele had an increased risk of high grade prostate cancer (Gleason score 8 or more, or poorly differentiated cancer) compared to those with the (tttta)4 allele (aOR=1.79, 95% Cl=1.08-2.97 and p =0.025). No significant difference in the serum levels of 6 steroid hormones or their metabolites was found in the presence or absence of the (tttta)4 allele. Our results suggest that the CYP11A1 polymorphism may have a significant influence on the development of advanced and/or high grade prostate cancer and the absence of the CYP11A1 (tttta)4 allele, i.e., the homozygosity for the (tttta)6 or longer allele, could be a useful marker for the prediction of disease progression of prostate cancer.
雄激素的生物合成和代谢与前列腺癌的发生和发展相关，这一点已得到广泛认可。人类CYP11A1基因（CYP11A1）编码P450scc酶，该酶介导性甾体激素合成的第一步。该基因在翻译起始位点上游528 bp处含有一个（tttta）n - 5 bp串联重复微卫星多态性，CYP11A1 mRNA水平可能受该多态性的调节。最近的研究表明，CYP11A1多态性中最短的（tttta）4等位基因缺失与多囊卵巢综合征风险以及多囊卵巢综合征患者的高雄激素状态相关。在我们纳入278例前列腺癌患者、213例良性前列腺增生（BPH）患者和299例男性对照的研究中，我们基于（tttta）4等位基因的存在可能增加前列腺癌发生或进展风险这一假设，探讨了CYP11A1多态性与前列腺癌之间的关联。此外，我们测量了156例男性对照受试者血清中6种甾体激素或其代谢产物（即睾酮、游离睾酮、雌酮、雌二醇、脱氢表雄酮和雄烯二酮）的水平，并对有和没有（tttta）4等位基因的受试者进行了比较。通过PCR扩增145 - 170 bp片段，随后进行聚丙烯酰胺凝胶电泳来评估该多态性。CYP11A1等位基因由4、6、7、8和9个（tttta）- 5 bp重复序列组成。前列腺癌患者与男性对照之间以及前列腺癌患者与BPH患者之间，就（tttta）4等位基因的存在而言，基因型频率无显著差异。然而，与疾病状态相关的基因型频率存在显著差异。与携带（tttta）4等位基因的前列腺癌患者相比，不携带（tttta）4等位基因的前列腺癌患者发生转移疾病（D期）的风险增加[校正比值比（aOR）=1.76，95%置信区间（Cl）=1.07 - 2.90，p =0.026]。与携带（tttta）4等位基因的患者相比，不携带（tttta）4等位基因的患者发生高级别前列腺癌（Gleason评分8分或更高，或低分化癌）的风险增加（aOR =1.79，95% Cl =1.08 - 2.97，p =0.025）。无论是否存在（tttta）4等位基因，血清中6种甾体激素或其代谢产物水平均无显著差异。我们的结果表明，CYP11A1多态性可能对晚期和/或高级别前列腺癌的发生有显著影响，CYP11A1（tttta）4等位基因缺失，即（tttta）6或更长等位基因的纯合性，可能是预测前列腺癌疾病进展的有用标志物。
